Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder
Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder
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DOI：
10.1001/jama.2015.10078
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发表时间：
2015-09-01
影响因子：
120.7
通讯作者：
Fernandez, Bridget A.
中科院分区：
文献类型：
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作者：
Tammimies, Kristiina;Marshall, Christian R.;Fernandez, Bridget A.
使用全基因组检测为自闭症谱系障碍（ASD）患者提供分子诊断需要更多的研究。目的：对异质组ASD患儿进行染色体微阵列分析（CMA）和全外显子组测序（WES），以确定发育性儿科诊所典型样本中这些检测的分子诊断率。设计、环境和参与者样本包括258名连续确定的无血缘关系的ASD儿童，他们接受了详细的评估，以确定基于主要先天性异常和轻微身体异常存在的形态学评分。这些孩子是2008年至2013年在加拿大纽芬兰和拉布拉多招募的。先证者按形态学严重程度依次分为基本、模糊和复杂3组（评分0- 3,4 -5,>= 6）。所有先证者都进行了CMA，对95个先证者-父母三人组进行了WES。在以人群为基础的ASD样本中，CMA和WES的总体分子诊断率分为3个表型组。258个先证者中，有24个（9.3%,95% CI, 6.1%-13.5%）接受了CMA的分子诊断，95个中有8个（8.4%,95% CI, 3.7%-15.9%）接受了WES的分子诊断。不同形态组间的产量有统计学差异。在同时接受CMA和WES检测的儿童中，具有可识别遗传病因的估计比例为15.8% （95% CI, 9.1%-24.7%； 15/95名儿童）。其中包括2名接受了两项检测的分子诊断的儿童。复方组的总产率显著高于精华组（两两比较，P = 0.002）。结论与相关性在异质性的ASD患儿样本中，CMA和WES的分子诊断率具有可比性，且在形态表型较复杂的患儿中，联合分子诊断率高于本质类患儿。如果在其他人群中重复，这些发现可能会为自闭症儿童分子诊断检测的适当选择提供信息。
IMPORTANCE The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study.OBJECTIVE To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic.DESIGN, SETTING, AND PARTICIPANTS The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and >= 6).EXPOSURES All probands underwent CMA, with WES performed for 95 proband-parent trios.MAIN OUTCOMES AND MEASURES The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups.RESULTS Of 258 probands, 24 (9.3%, 95% CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95% CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95% CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P =.002).[Graphics]CONCLUSIONS AND RELEVANCE Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.